title: Polyalanine repeat polymorphism in RUNX2 is associated with site-specific fracture in post-menopausal females.
abstract: Runt related transcription factor 2 (RUNX2) is a key regulator of osteoblast differentiation. Several variations within the RUNX2 gene have been found to be associated with significant changes in BMD, which is a major risk factor for fracture. In this study we report that an 18 bp deletion within the polyalanine tract (17A>11A) of RUNX2 is significantly associated with fracture. Carriers of the 11A allele were found to be nearly twice as likely to have sustained fracture. Within the fracture category, there was a significant tendency of 11A carriers to present with fractures of distal radius and bones of intramembranous origin compared to bones of endochondral origin (p = 0.0001). In a population of random subjects, the 11A allele was associated with decreased levels of serum collagen cross links (CTx, p = 0.01), suggesting decreased bone turnover. The transactivation function of the 11A allele showed a minor quantitative decrease. Interestingly, we found no effect of the 11A allele on BMD at multiple skeletal sites. These findings suggest that the 11A allele is a biologically relevant polymorphism that influences serum CTx and confers enhanced fracture risk in a site-selective manner related to intramembranous bone ossification.
authors.affiliation: School of Medical Sciences, Griffith University, Gold Coast, Queensland, Australia.
authors.forename: Nigel A
authors.initials: NA
authors.lastname: Morrison
authors.forename: Alexandre S
authors.initials: AS
authors.lastname: Stephens
authors.forename: Motomi
authors.initials: M
authors.lastname: Osato
authors.forename: Julie A
authors.initials: JA
authors.lastname: Pasco
authors.forename: Nicolette
authors.initials: N
authors.lastname: Fozzard
authors.forename: Gary S
authors.initials: GS
authors.lastname: Stein
authors.forename: Patsie
authors.initials: P
authors.lastname: Polly
authors.forename: Lyn R
authors.initials: LR
authors.lastname: Griffiths
authors.forename: Geoff C
authors.initials: GC
authors.lastname: Nicholson
mesh_terms: D000483:Alleles; D001483:Base Sequence; D015519:Bone Density; D050659:Core Binding Factor Alpha 1 Subunit / Q000235:genetics*; D017931:DNA Primers; D005260:Female; D050723:Fractures, Bone / Q000235:genetics*; D020022:Genetic Predisposition to Disease; D006801:Humans; D008875:Middle Aged; D010455:Peptides / Q000235:genetics*; D016133:Polymerase Chain Reaction; D011110:Polymorphism, Genetic; D017698:Postmenopause
chemical_list: D050659:Core Binding Factor Alpha 1 Subunit; D017931:DNA Primers; D010455:Peptides; C493709:RUNX2 protein, human; C019529:polyalanine